For the past 10 years, investigators at Emory have been studying the sources, regulation and functional implications of reactive oxygen species (ROS) in vascular biology and disease. Our PPG application builds on this expertise to test the overall hypothesis that ROS within the vessel wall are central mediators of vascular disease, and represent a unifying mechanism whereby different risk factors modify vessel function. In Project 1, Dr. Griendling will investigate the role of ROS in mediating smooth muscle dysfunction in type 2 diabetes. Her project involves studying the molecular mechanisms by which angiotensin II exacerbates insulin resistance, with a focus on the redox-sensitive phosphoinositide-dependent kinase-1 and the novel NAD(P)H oxidase protein nox4. In Project 2, Dr. Galis will investigate the hypothesis that distortion of flow patterns is related to excessive production of ROS, which in turn contributes to remodeling of the atherosclerotic plaque. She will focus on the regulation of matrix metalloproteinase (MMP) expression by shear and oxidative stress, and define the relationship between these two stimuli both in vitro and in vivo using MMP-9 promoter/lacZ mice. In Project 3, Dr. Harrison will examine the molecular events by which laminar shear stress controls endothelial nitric oxide synthase (eNOS) expression and thus regulates inflammatory events. He will test the novel hypothesis that acute exposure to laminar shear induces NFkappaB activation, which increases expression of the endothelial nitric oxide synthase (eNOS) and increases the production of NO, leading to inhibition of NFkappaB and inflammatory responses over the long term. Dr. Jo, in Project 4, plans to study the role of bone morphogenic protein-4 (BMP-4) in atherogenesis. He will examine the regulation of this protein by oxidative and shear stress both in vitro and in vivo, and will define the downstream signaling mechanisms by which BMP-4 exerts its proinflammatory effects. All projects will be supported by two cores, one led by Dr. Dikalov that is designed to provide state of the art ESR measurements of ROS, and one led by Dr. Hilenski, who will furnish expertise in confocal microscopy and imaging of ROS in cells and tissues. Overall this research program will provide substantial new information defing the integrated mechanisms by which ROS contribute to vascular disease. Ultimately, this research may establish new unifying concepts linking conditions that alter vascular oxidant stress to the molecular processes underlying vasculopathies.